Treatment with histone deacetylase (HDAC) inhibitors can improve the symptoms of Huntington’s disease in a mouse model of the disorder – and can improve their untreated sons’ future symptoms as well, an example of a so-called transgenerational drug effect.
“This is the first study to show the transgenerational effect [of a treatment] is beneficial,” senior author Beth Thomas of The Scripps Research Institute told BioWorld Today.
The findings broaden the view of transgenerational effects. Currently, it would perhaps be an oversimplification to summarize such research as “ways your mother screws you up” – but not all that much of one.
Studies have focused on the way parental actions before conception can harm their future offspring – stress leads to obesity, drug abuse to multiple effects including a rewiring of the brain’s reward system, making offspring more vulnerable to drugs of abuse themselves.
And “people tend to think about only maternal inheritance,” though transgenerational effects such as poor health in people whose parents were born during the Dutch famine of World War II, influenced the fate of children whose fathers suffered through it as well.
In fact, one study reported that for the grandchildren of such individuals, it was only the grandfather’s malnourishment, not the grandmother’s, which affected birth weight.
Biologically, such transgenerational effects are due to epigenetic changes – changes not to the sequence of DNA itself, but to tags both on the DNA itself, and on the histone proteins that provide structural support and organization to DNA strands.
Epigenetic drugs are being tested in many cancers, as well as neurological disorders. Already approved is Merck & Co. Inc.’s Zolinza (vorinostat) for cutaneous T-cell lymphoma. Several HDAC inhibitors are in phase III trials, mostly for cancer. But one such drug, Siena Biotech SpA’s selisistat, is also being tested in Huntington’s disease.
Huntington’s disease is a neurodegenerative disorder that leads to motor, cognitive and psychiatric symptoms. It is caused by a mutation in a single protein, the huntingtin protein, which causes the protein to clump, killing nerve cells and, ultimately, the affected individual.
Epigenetic mechanisms play a role in Huntington’s disease, though their importance relative to other mechanisms and their clinical significance is not clear.
But “there is a defect in histone acetylation, which leads to compressed chromatin and less gene expression” in Huntington’s disease, Thomas said.
Which genes are affected downstream by those changes had not been worked out in detail and so in their work, which appeared in the Dec. 22, 2014, issue of the Proceedings of the National Academy of Sciences, Thomas and her colleagues used gene expression profiling by microarrays to identify those downstream genes. The experiments were performed on mice that are engineered to have the human gene for mutant huntingtin.
In the mice, treatment with an HDAC 4 inhibitor improved the treated animals’ motor symptoms, as well as decreasing their anxiety. And when the animals had offspring after treatment, the sons of treated males showed the same benefits, even though they themselves did not receive the drug.
The effects of the treatment are specific to male offspring because methylation affects a number of genes on the Y chromosome. Thomas does not believe that the effect is specific to fathers, though.
“Paternal effects are more straightforward,” to study, she said. Treating a pregnant female can amount to treating three generations – the animal, her female offspring, and her female offspring’s oocytes, which are already present in the developing embryo.
That can make sorting out which generation a drug is actually acting on a bit of a doozy. “But you certainly can do these experiments in females. You just have to look further down the line for effects,” which is one thing she and her team plan to do.
The team also wants to test other types of drugs. “There’s a whole slew of drugs being studied for their epigenetic mechanisms,” Thomas said, and some of those drugs might also show transgenerational effects.